Mesothelin as a biomarker for clinical management of esophageal adenocarcinoma

间皮素作为食管腺癌临床治疗的生物标志物

• 批准号: 8386226
• 负责人: Prasad S. Adusumilli
• 金额: $ 23.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386226
• 关键词: Adjuvant Therapy; Biological; Biological Markers; Blood; Blood Tests; Cancer Patient; Cell surface; Cleaved cell; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Data; Databases; Differentiation Antigens; Disease; Esophageal; Esophageal Adenocarcinoma; Evaluation; Excision; Image; Immunohistochemistry; Incidence; Individual; Intervention; Lymph Node Involvement; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measures; Memorial Sloan-Kettering Cancer Center; Mesothelioma; Modality; N-terminal; Operative Surgical Procedures; Outcome; Pathological Staging; Patients; Peptides; Protocols documentation; Publications; Radiation therapy; Recording of previous events; Recurrence; Research Infrastructure; Research Proposals; Resected; Resistance; Sampling; Serum; Staging; Survival Rate; Testing; Therapeutic; Time; Tissues; Tumor Burden; Validation; Widespread Disease; advanced disease; base; cancer cell; candidate selection; design; high risk; improved; instrument; mesothelin; migration; outcome forecast; pre-clinical; prospective; research clinical testing; response; standard of care; treatment response; tumor

DESCRIPTION (provided by applicant): A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Esophageal Adenocarcinoma (EAC) Patients The incidence of esophageal adenocarcinoma (EAC) is rising at an annual rate of 8%. Most EAC patients present at an advanced stage disease with an overall 5-year survival rate of 10%. Of the patients who present with potentially curable disease, majority will already have local-regional advanced disease. Although combined modality treatment, the current standard of care for locally advanced disease, improves survival, lack of accurate clinical evaluation of tumor burden and treatment response is a significant limitation in selecting appropriate treatment in a timely fashion. In spite of the radiographic and endoscopic imaging, one in four patients with a presumed early-stage disease are found to have more extensive disease (T3 or N1) at the time of surgery. These patients would have benefited from multimodality therapy. In patients treated with neo- adjuvant therapy for local-regional advanced disease, assessment of therapy response remains inaccurate. Identification and validation of a biomarker that reflects tumor burden, therapy response, and recurrence will be highly valuable for the clinical management and clinical trials of EAC patients. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of EAC patients. Mesothelin is a cell surface tumor-differentiation antigen, the N-terminal of which is cleaved and secreted into blood, measured as serum soluble mesothelin-related peptide (SMRP). Increased SMRP levels are demonstrated in mesothelioma, pancreatic and ovarian cancer patients. Recent publications have demonstrated that the level of SMRP correlates with tumor load, therapy response, and prognosis in mesothelioma patients. We propose: Specific Aim 1: To prospectively evaluate whether serum SMRP levels correlate with (a) clinical staging, (b) response to neo-adjuvant therapy, and (c) disease recurrence in surgically resected EAC patients. Specific Aim 2: To prospectively investigate whether tissue mesothelin expression (a) pre chemo-radiation therapy is a predictor of poor therapy response, and (b) post-resection is a predictor of poor survival. The novelty and impact of this carefully designed prospective proposal extends beyond biomarker study in testing the utility of mesothelin as a marker of Barrett's transformation to EAC; it is immediately translational to benefit 15,000 patients with EAC. PUBLIC HEALTH RELEVANCE: A simple predictive instrument to identify early-stage esophageal adenocarcinoma patients at higher risk for poor therapy response and recurrence; therefore the most likely candidates for selection of therapeutic modality or aggressive surveillance will benefit. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of esophageal adenocarcinoma patients.

描述（由申请人提供）：评估间皮素作为食管腺癌 (EAC) 患者临床管理生物标志物的前瞻性临床试验食管腺癌 (EAC) 的发病率以每年 8% 的速度上升。大多数 EAC 患者已处于晚期疾病，总体 5 年生存率为 10%。在患有潜在可治愈疾病的患者中，大多数已经患有局部晚期疾病。尽管联合治疗（目前局部晚期疾病的护理标准）可以提高生存率，但缺乏对肿瘤负荷和治疗反应的准确临床评估是及时选择适当治疗的重大限制。尽管进行了放射照相和内窥镜成像，四分之一的假定患有早期疾病的患者在手术时发现患有更广泛的疾病（T3或N1）。这些患者将受益于多学科治疗。在接受新辅助治疗的局部晚期疾病的患者中，治疗反应的评估仍然不准确。反映肿瘤负荷、治疗反应和复发的生物标志物的鉴定和验证对于 EAC 患者的临床管理和临床试验非常有价值。 在这项研究计划中，基于我们有希望的回顾性数据，我们旨在研究血清和组织间皮素作为生物标志物，以改善 EAC 患者的临床管理。间皮素是一种细胞表面肿瘤分化抗原，其 N 末端被切割并分泌到血液中，以血清可溶性间皮素相关肽 (SMRP) 的形式进行测量。间皮瘤、胰腺癌和卵巢癌患者中 SMRP 水平升高。最近的出版物表明，SMRP 水平与间皮瘤患者的肿瘤负荷、治疗反应和预后相关。我们建议： 具体目标 1：前瞻性评估手术切除的 EAC 患者中血清 SMRP 水平是否与 (a) 临床分期、(b) 对新辅助治疗的反应和 (c) 疾病复发相关。具体目标 2：前瞻性研究组织间皮素表达是否 (a) 放化疗前是治疗反应不良的预测因素，(b) 切除后是不良生存的预测因素。这一精心设计的前瞻性提案的新颖性和影响力超出了生物标志物研究的范围，用于测试间皮素作为 Barrett 向 EAC 转化的标志物的效用；是立即 使 15,000 名 EAC 患者受益。 公共卫生相关性：一种简单的预测工具，可识别治疗反应不佳和复发风险较高的早期食管腺癌患者；因此，最有可能选择治疗方式或积极监测的候选人将会受益。在这项研究计划中，基于我们有希望的回顾性数据，我们旨在研究血清和组织间皮素作为生物标志物，以改善食管腺癌患者的临床管理。